1. Field of the Invention
This invention relates to a new, efficient process for the production of 7.beta.-[(2D-2-amino-2-carboxy)-ethylthioacetamido]-7.alpha.-methoxy-3-[(1 -methyl-1H-tetrazole-5-yl)thiomethyl]-3-cephem-4-carboxylic acid of the formula (I) ##STR1## which is useful as an antibacterially effective cephalosporine derivative.
2. Description of the Prior Art
The compound of the formula (I) is a new 7-methoxycephalosporine derivative which was synthetized at the first time by some of the present inventors (see German DT-OS P No. 29 50 990, Belgian Pat. No. 880,656; and co-pending U.K.. patent application No. 79 43159 and U.S. patent application Ser. No. 104,220) and which is useful as an antibacterial agent having a high "in vivo" antibacterial activity against gram-positive bacteria and particularly against gram-negative bacteria.
According to the methods of the above German DT-OS P No. 29 50 990 or Belgian Pat. No. 880,656, the compound of the formula (I) is prepared using such a starting compound containing a cephem nucleus previously bearing the 7.alpha.-methoxy substituent, either by condensing, for example, the 7-bromoacetyl derivative of 7.beta.-amino-7.alpha.-methoxy-3-[(1-methyl-1H-tetrazole-5-yl)thiomethyl]- 3-cephem-4-carboxylic acid, with D-cysteine, or by condensing the 7-bromoacetyl derivative of 7.beta.-amino-7.alpha.-methoxy-cephalosporanic acid with D-cysteine, followed by introduction of the tetrazolylthiomethyl group in place of the 3-acetoxymethyl group of the resulting intermediate condensation product.
However, these methods of the above German DT-OS or Belgian patent always employ as the initial compound a compound containing the 7.alpha.-methoxycephem nucleus which is more expensive than the cephem compound containing no 7.alpha.-methoxy substituent, and hence these methods are not economic for the commercial production of the desired compound of the formula (I) in that the expensive initial 7.alpha.-methoxycephem compound is, in fact, usually lost in portions in the respective stages for conversion of the initial 7.alpha.-methoxycephem compound into the ultimately desired compound of the formula (I); so that the 7.alpha.-methoxycephem nucleus present in the initial compound employed is not utilized to a full degree in the final product of the formula (I). Besides, the acetoxymethyl substituent attaching to the 3-position of the 7.alpha.-methoxycephem nucleus is usually less active for the nucleophilic substitutive reaction than that of the cephem nucleus not containing the 7.alpha.-methoxy group, and therefore the method of said German DT-OS or Belgian patent comprising condensing the 7-bromo-acetyl derivative of 7.alpha.-methoxycephalosporanic acid with D-cysteine and subsequently introducing the tetrazolylthiomethyl group in place of the 3-acetoxymethyl group of the resultant condensation product to produce the corresponding 3-tetrazolylthiomethyl derivative which is the desired compound of the formula (I) always gives the final product of the formula (I) in an unfavorable yield.
We have paid an attention on these drawbacks of the methods we firstly developed, and we have made extensively further researches to find out that such a cephem compound containing a cephem nucleus previously having the desired (1-methyl-1H-tetrazole-5-yl)thiomethyl substituent and the [(2D-2-amino-2-carboxyl)-ethylthioacetamido] substituent, respectively at the 3- and 7-positions thereof corresponding to those of the final product of the formula (I) can be prepared at first, that the cephem compound so prepared can be used as the starting material into which the 7.alpha.-methoxy group is to be introduced at the 7-position of the cephem nucleus thereof in a subsequent stage and that the 7.alpha.-methoxylation of the cephem nucleus can be achieved in a high efficiency with preventing undesired side-reactions when particular methoxylation reagents are selected and the excessive methoxylation reagents remaining after the methoxylation reaction are immediately inactivated by selected agents. On the basis of this finding, we have desired the new process of this invention.
An object of this invention is to provide a new process for the production of the particular 7.alpha.-methoxycephem compound of the aforesaid formula (I) which can be carried out in an economic and facile way and which can give a high yield of the desired 7.alpha.-methoxycephem compound of the formula (I). The other objects of this invention will be clear from the following descriptions.